The present invention relates to a production method of oxyimino-alkanoic acid derivatives having an anti-diabetic activity.
As a production method of oxyimino-alkanoic acid derivatives involving arylmethylation of the oxime moiety of oxime alkanoic acid, JP-A-10-168071 and JP-A-8-176127 disclose production methods of thiazole acetic acid derivatives used as a side chain of cefem antibiotics. According to the Examples of these publications, potassium carbonate, sodium carbonate or lithium carbonate is used as a base for introducing triphenylmethyl into the oxime moiety by the reaction of an oxime alkanoic acid derivative with triphenylmethyl chloride.
As a production method of oxyimino-alkanoic acid amide derivatives involving arylmethylation of the oxime moiety of oxime alkanoic acid amide, Tetrahedron, vol. 42, p. 6511 (1986) discloses a production method of a synthetic intermediate for xcex1,xcex2-epoxytryptophan derivatives. According to this method, 1,2-dimethoxyethane is used as a solvent for the reaction of oxime alkanoic acid amide with benzyl bromide.
The present inventors found that, when a weak base, such as alkali metal carbonate and the like disclosed in the aforementioned publications, is used for producing a compound represented by the formula (III) 
wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94NR6xe2x80x94(R6 is a hydrogen atom or an optionally substituted alkyl group); n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR7xe2x80x94(R7 is a hydrogen atom or an optionally substituted alkyl group); ring A is a benzene ring optionally having 1 to 3 additional substituents; p is an integer of 1 to 8; R2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; and R4 and R5 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, or R4 may be bonded to R2 to form a ring, or a salt thereof, a by-product occurs to lower the yield of the objective oxyimino-alkanoic acid derivative, potentially contaminating the final product as a related substance. It was also clarified that the removal thereof requires further purification by separation using silica gel column chromatography and the like, making operation complicated, and may adversely affect the environment through the disposal of a large amount of waste silica gel and the like.
The present inventors also found that, when a low polar solvent such as 1,2-dimethoxyethane and the like disclosed in the aforementioned papers, is used for producing a compound represented by the formula (V) 
wherein R8 and R9 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R8 and R9 may be bonded to form a ring, and other symbols are as defined above, or a salt thereof, oxime alkanoic acid amide precipitates out in the reaction mixture as a metal salt, which significantly prevents progress of the reaction, lowers the reaction yield and causes residual starting materials. It was also clarified that, for removal of the residual starting materials, further purification by separation using silica gel chromatography and the like is necessary, which in turn makes operation complicated and possibly affects the environment adversely through the disposal of a large amount of waste silica gel and the like.
Under the circumstances, there is a strong demand for the development of an industrially advantageous and environmentally thoughtful production method of oxyimino-alkanoic acid derivatives, which can be put to use for practical production.
In an attempt to solve the above-mentioned problems, the present inventors have conducted intensive studies of an industrially advantageous production method of oxyimino-alkanoic acid derivatives, and found that the use of a metal alkoxide, which is a strong base, for the production of a compound represented by the above-mentioned formula (III) or a salt thereof by arylmethylation of the oxime moiety of oxime alkanoic acid suppresses formation of by-products. They have also found that the use of amides (polar solvents) as a reaction solvent for the production of oxyimino-alkanoic acid amide derivatives represented by the above-mentioned formula (V), by arylmethylation of the oxime moiety of oxime alkanoic acid amide increases reaction rates and decreases remaining starting material.
The present inventors have further developed the studies based on such findings, and, as a result, completed the present invention directed to a production method of oxyimino-alkanoic acid derivatives, which is an industrially advantageous and environmentally thoughtful production method that produces the derivatives having high quality in a high yield without purification by silica gel column chromatography.
Accordingly, the present invention provides
(1) a production method of a compound represented by the formula (III) 
xe2x80x83wherein
R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94NR6xe2x80x94(R6 is a hydrogen atom or an optionally substituted alkyl group);
n is an integer of 1 to 3;
Y is an oxygen atom, a sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR7xe2x80x94(R7 is a hydrogen atom or an optionally substituted alkyl group);
ring A is a benzene ring optionally having 1 to 3 additional substituents;
p is an integer of 1 to 8;
R2 is a hydrogen atom or an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
q is an integer of 0 to 6;
m is 0 or 1; and
R4 and R5 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, or R may be bonded to R2 to form a ring,
xe2x80x83or a salt thereof, which comprises reacting a compound represented by the formula (I) 
xe2x80x83wherein Z is a halogen atom or OSO2R10 (R10 is an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which is optionally substituted by alkyl group having 1 to 4 carbon atoms), and other symbols in the formula are as defined above, or a salt thereof, with a compound represented by the formula (II) 
xe2x80x83wherein the symbols in the formula are as defined above, or a salt thereof, in an amide in the presence of a metal alkoxide,
(2) the production method of the above-mentioned (1), wherein the metal alkoxide is an alkali metal C1-4 alkoxide,
(3) the production method of the above-mentioned (2), wherein the alkali metal C1-4 alkoxide is sodium tert-butoxide,
(4) the production method of the above-mentioned (1), wherein the amide is N,N-dimethylacetamide, N,N-dimethylformamide, 1-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone,
(5) the production method of the above-mentioned (4), wherein the amide is N,N-dimethylacetamide,
(6) the production method of the above-mentioned (1), wherein the metal alkoxide is sodium tert-butoxide and the amide is N,N-dimethylacetamide,
(7) the production method of the above-mentioned (1), wherein the compound represented by the formula (III) is (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanoic acid or a salt thereof,
(8) the production method of the above-mentioned (1), wherein the compound represented by the formula (III) is (E)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid or a salt thereof,
(9) a production method of a compound represented by the formula (V) 
xe2x80x83wherein R8 and R9 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R8 and R9 may be bonded to form a ring, and other symbols are as defined above, or a salt thereof, which comprises amidating the compound represented by the formula (III), which is produced according to the production method of (1) above, or a salt thereof,
(10) the production method of the above-mentioned (9), wherein the compound represented by the formula (V) is (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutylamide or a salt thereof,
(11) a production method of a compound represented by the formula (V) 
xe2x80x83wherein R1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94NR6xe2x80x94(R6 is a hydrogen atom or an optionally substituted alkyl group); n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR7xe2x80x94(R7 is a hydrogen atom or an optionally substituted alkyl group); ring A is a benzene ring optionally having 1 to 3 additional substituents; p is an integer of 1 to 8; R2 is a hydrogen atom or an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R8 and R9 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R8 and R9 may be bonded to form a ring; and R4 and R5 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, or R4 may be bonded to R2 to form a ring, or a salt thereof, which comprises reacting a compound represented by the formula (I) 
xe2x80x83wherein Z is a halogen atom or OSO2R10 (R10 is an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms which is optionally substituted by alkyl group having 1 to 4 carbon atoms); and other symbols are as defined above, or a salt thereof, with a compound represented by the formula (IV) 
xe2x80x83wherein each symbol in the formula is as defined above, or a salt thereof, in an amide in the presence of a metal carbonate,
(12) the production method of the above-mentioned (11), wherein the metal carbonate is an alkali metal carbonate,
(13) the production method of the above-mentioned (11), wherein the amide is N,N-dimethylacetamide, N,N-dimethylformamide, 1-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone,
(14) the production method of the above-mentioned (11), wherein the compound represented by the formula (V) is (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutylamide or a salt thereof.
(1) Definition of R1 
As the hydrocarbon group of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 in the formulas, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an alicyclic-aliphatic hydrocarbon group, an aromatic aliphatic hydrocarbon group and an aromatic hydrocarbon group are exemplified. These hydrocarbon groups preferably have 1 to 14 carbon atoms.
(1-1) Definition of Hydrocarbon Group for R1 
As the aliphatic hydrocarbon group, an aliphatic hydrocarbon group having 1 to 8 carbon atoms is preferable. As the aliphatic hydrocarbon group, for example, a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms (e.g., alkyl group and the like), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl and the like; and an unsaturated aliphatic hydrocarbon group having 2 to 8 carbon atoms (e.g., alkenyl group having 2 to 8 carbon atoms, alkadienyl group having 4 to 8 carbon atoms, alkenylalkynyl group having 2 to 8 carbon atoms, alkadiynyl group having 4 to 8 carbon atoms and the like), such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like, are mentioned.
As the alicyclic hydrocarbon group, an alicyclic hydrocarbon group having 3 to 7 carbon atoms is preferable. As the alicyclic hydrocarbon group, for example, a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms (e.g., cycloalkyl group and the like), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; and an unsaturated alicyclic hydrocarbon group having 5 to 7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienyl group and the like), such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl and the like, are mentioned.
As the alicyclic-aliphatic hydrocarbon group, the groups (e.g., cycloalkyl-alkyl group, cycloalkenyl-alkyl group and the like) are mentioned, wherein the above-mentioned alicyclic hydrocarbon group and an aliphatic hydrocarbon group are bonded. Of the alicyclic-aliphatic hydrocarbon groups, one having 4 to 9 carbon atoms is preferable. As the alicyclic-aliphatic hydrocarbon group, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl and the like are mentioned.
As the aromatic aliphatic hydrocarbon group, an aromatic aliphatic hydrocarbon group having 7 to 13 carbon atoms (e.g., aralkyl group having 7 to 13 carbon atoms, arylalkenyl group having 8 to 13 carbon atoms, and the like) is preferable. As the aromatic aliphatic hydrocarbon group, for example, phenylalkyl having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl and the like; naphthylalkyl having 11 to 13 carbon atoms, such as xcex1-naphthylmethyl, xcex1-naphthylethyl, xcex2-naphthylmethyl, xcex2-naphthylethyl and the like; phenylalkenyl having 8 to 10 carbon atoms such as styryl and the like; and naphthylalkenyl having 12 or 13 carbon atoms such as 2-(2-naphthylvinyl) and the like are mentioned.
As the aromatic hydrocarbon group, an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., aryl group and the like) is preferable. As the aromatic hydrocarbon group, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like are mentioned. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
(1-2) Definition of Heterocyclic Group for R1 
As the heterocyclic group of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 in the formulas, a 5 to 7-membered monocyclic heterocyclic group or fused heterocyclic group, containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom is mentioned. As the fused heterocycle, for example, a fused ring of these 5 to 7-membered monocyclic heterocycles with a 6-membered ring containing 1 or 2 nitrogen atoms, benzene ring or a 5-membered ring containing one sulfur atom is mentioned.
Specific examples of the heterocyclic group include aromatic heterocyclic groups, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl, 2-quinoxalyl, 2-benzoxazolyl, 2-benzothiazolyl, benzimidazol-1-yl, benzimidazol-2-yl, indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl and the like; a non-aromatic heterocyclic group, such as 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, hexamethylenimin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl and the like; and the like are mentioned.
The heterocyclic group is preferably pyridyl, oxazolyl, thiazolyl, benzoxazolyl or benzothiazolyl.
(1-3) Definition of Substituent for Hydrocarbon Group and/or Heterocyclic Group for R1 
In the formulas, the hydrocarbon group and heterocyclic group represented by R1 optionally have 1 to 5, preferably 1 to 3, substituents at substitutable positions. As the substituent, for example, optionally substituted aliphatic hydrocarbon group, optionally substituted alicyclic hydrocarbon group, optionally substituted aromatic hydrocarbon group, optionally substituted aromatic heterocyclic group, optionally substituted non-aromatic heterocyclic group, halogen atom, nitro group, optionally substituted amino group, optionally substituted acyl group, optionally substituted hydroxy group, optionally substituted thiol group, and optionally esterified or amidated carboxyl group are mentioned.
With respect to the xe2x80x9coptionally substituted aliphatic hydrocarbon groupxe2x80x9d, xe2x80x9coptionally substituted alicyclic hydrocarbon groupxe2x80x9d, xe2x80x9coptionally substituted aromatic hydrocarbon groupxe2x80x9d, xe2x80x9coptionally substituted aromatic heterocyclic groupxe2x80x9d and xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d, the substituent therefor is exemplified by C1-6 alkyl group, C1-6 alkoxy group, halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), nitro group, C1-6 haloalkyl group and C1-6 haloalkoxy group. The number of substituent is, for example, 1 to 3.
As the aliphatic hydrocarbon group, a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, such as alkyl group, alkenyl group, alkynyl group and the like, are mentioned.
Preferable examples of the alkyl group include an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
Preferable examples of the alkenyl group include an alkenyl group having 2 to 10 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.
Preferable examples of the alkynyl group include an alkynyl group having 2 to 10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
As the alicyclic hydrocarbon group, a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, such as cycloalkyl group, cycloalkenyl group, cycloalkadienyl group and the like, are mentioned.
Preferable examples of the cycloalkyl group include a cycloalkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and the like.
Preferable examples of the cycloalkenyl group include a cycloalkenyl group having 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
Preferable examples of the cycloalkadienyl group include a cycloalkadienyl group having 4 to 10 carbon atoms, such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like.
Preferable examples of the aromatic hydrocarbon group include an aromatic hydrocarbon group having 6 to 14 carbon atoms (e.g., aryl group and the like), such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
Preferable examples of the aromatic heterocyclic group include a 5 to 7-membered aromatic monocyclic heterocyclic group, containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like; a bicyclic or tricyclic aromatic fused heterocycle having 3 to 13 carbon atoms, which contains, as a ring-constituting atom besides carbon atom, 1 to 5 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbonylyl, xcex2-carbonylyl, xcex3-carbonylyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and the like; and the like.
Preferable examples of the non-aromatic heterocyclic group include those having 2 to 10 carbon atoms, which contain, as a ring-constituting atom besides carbon atom, 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom, such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperidino, morpholino, thiomorpholino and the like.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine, with preference given to fluorine and chlorine.
As the optionally substituted amino group, for example, an amino group optionally mono- or di-substituted by an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an acyl group having 1 to 13 carbon atoms (e.g., alkanoyl group having 2 to 10 carbon atoms, arylcarbonyl group having 7 to 13 carbon atoms and the like) or aryl group having 6 to 12 carbon atoms is mentioned. The acyl group here is the same as the acyl group of the xe2x80x9coptionally substituted acyl groupxe2x80x9d to be mentioned below.
As the substituted amino group, for example, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino, N-methyl-N-phenylamino and the like are mentioned.
The acyl group of the optionally substituted acyl group includes, for example, an acyl group having 1 to 13 carbon atoms, such as formyl, and a group wherein alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms or an aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl and the like) is bonded to a carbonyl group, and the like.
Preferable examples of acyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like.
The acyl group may have 1 to 3 substituents at substitutable positions. Examples of the substituent include alkyl group having 1 to 3 carbon atoms, such as alkoxy group having 1 to 3 carbon atoms, halogen (e.g., fluorine, chlorine, iodine and the like), nitro, hydroxy, amino and the like.
The acyl group in a different form is represented by the following formula
xe2x80x94COR11, xe2x80x94SO2R14, xe2x80x94SOR15 or xe2x80x94PO3R16R17
wherein R11, R14, R15, R16 and R17 are the same or different and each is an optionally substituted hydrocarbon group.
Examples of the hydrocarbon group of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R11, R14 , R15, R16 and R17 include an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms and an aryl group having 6 to 12 carbon atoms. Examples of the substituent of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d include C1-6 alkyl group (except that wherein the hydrocarbon group is an alkyl group), C1-6 alkoxy group, halogen atom (e.g., fluorine, chlorine, bromine, iodine and the like), nitro group, C1-6 haloalkyl group and C1-6 haloalkoxy group. The number of substituent is, for example, 1 to 3.
In the optionally substituted hydroxy group, the substituted hydroxy group is exemplified by an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted aralkyloxy group, an optionally substituted acyloxy group, an optionally substituted aryloxy group and the like.
Preferable examples of the alkoxy group include an alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
Preferable examples of the alkenyloxy group include an alkenyloxy group having 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and the like.
Preferable examples of the aralkyloxy group include an aralkyloxy group having 7 to 10 carbon atoms, such as phenyl-C1-4 alkyloxy (e.g., benzyloxy, phenethyloxy and the like) and the like.
Preferable examples of the acyloxy group include an acyloxy group having 2 to 13 carbon atoms, more preferably alkanoyloxy having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and the like) and the like.
Preferable examples of the aryloxy group include an aryloxy group having 6 to 14 carbon atoms, such as phenoxy, naphthyloxy and the like.
The above-mentioned alkoxy group, alkenyloxy group, aralkyloxy group, acyloxy group and aryloxy group may have 1 or 2 substituents at substitutable positions. Examples of such substituent include halogen (e.g., fluorine, chlorine, bromine and the like), alkoxy group having 1 to 3 carbon atoms and the like. As the substituted aryloxy group, for example, 4-chlorophenoxy, 2-methoxyphenoxy and the like are mentioned.
In the optionally substituted thiol group, the substituted thiol group includes, for example, alkylthio, cycloalkylthio, aralkylthio, acylthio, arylthio, heteroarylthio and the like.
Preferable examples of the alkylthio group include an alkylthio group having 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec.-butylthio, t.-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like.
Preferable examples of the cycloalkylthio group include a cycloalkylthio group having 3 to 10 carbon atoms, such as cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
Preferable examples of the aralkylthio group include an aralkylthio group having 7 to 10 carbon atoms, such as phenyl-C1-4 alkylthio (e.g., benzylthio, phenethylthio and the like) and the like.
Preferable examples of the acylthio group include an acylthio group having 2 to 13 carbon atoms, more preferably an alkanoylthio group having 2 to 4 carbon atoms (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio and the like) and the like.
Preferable examples of the arylthio group include an arylthio group having 6 to 14 carbon atoms, such as phenylthio, naphthylthio and the like.
Preferable examples of the heteroarylthio group include, in addition to 2-pyridylthio, 3-pyridylthio and the like, 2-imidazolylthio, 1,2,4-triazol-5-ylthio and the like.
In the optionally esterified carboxyl group, the esterified carboxyl group is, for example, alkoxycarbonyl group having 2 to 5 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like), aralkyloxycarbonyl group having 8 to 10 carbon atoms (e.g., benzyloxycarbonyl and the like), aryloxycarbonyl group having 7 to 15 carbon atoms (e.g., phenoxycarbonyl, p-tolyloxycarbonyl and the like) which is optionally substituted by 1 or 2 alkyl groups having 1 to 3 carbon atoms, and the like.
In the optionally amidated carboxyl group, the amidated carboxyl group is, for example, a group represented by the formula:
xe2x80x94CON(R12)(R13)
wherein R12 and R13 are the same or different and each is hydrogen atom, optionally substituted hydrocarbon group or optionally substituted heterocyclic group.
As used herein, the hydrocarbon group of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R12 and R13 and the heterocyclic group of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R12 and R13 are each exemplified by aliphatic hydrocarbon group, alicyclic hydrocarbon group, aromatic hydrocarbon group and heterocyclic group, which have been exemplified above for the xe2x80x9chydrocarbon group of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1xe2x80x9d and the xe2x80x9cheterocyclic group of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1xe2x80x9d. The hydrocarbon group and heterocyclic group may have 1 to 3 substituents at substitutable positions. Examples of such substituent include halogen (e.g., fluorine, chlorine, bromine, iodine and the like), alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms and the like.
In the formulas, the substituent of the hydrocarbon group and heterocyclic group represented by R1 is preferably an alkyl group having 1 to 10 carbon atoms, an aromatic heterocyclic group and an aryl group having 6 to 14 carbon atoms. More preferably, it is alkyl having 1 to 3 carbon atoms, furyl, thienyl, phenyl or naphthyl.
When the substituent of the hydrocarbon group and heterocyclic group represented by R1 is alicyclic hydrocarbon group, aromatic hydrocarbon group, aromatic heterocyclic group or non-aromatic heterocyclic group, it may additionally have one or more, preferably 1 to 3, substituents. Examples of such substituent include, for example, alkyl group having 1 to 6 carbon atoms, alkenyl group having 2 to 6 carbon atoms, cycloalkyl group having 3 to 10 carbon atoms, aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl and the like), aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl and the like), non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl, piperazinyl and the like), aralkyl group having 7 to 9 carbon atoms, amino group, amino group mono- or di-substituted by alkyl group having 1 to 4 carbon atoms or acyl group having 2 to 8 carbon atoms (e.g., alkanoyl group and the like), amidino group, acyl group having 2 to 8 carbon atoms (e.g., alkanoyl group and the like), carbamoyl group, carbamoyl group mono- or di-substituted by alkyl group having 1 to 4 carbon atoms, sulfamoyl group, sulfamoyl group mono- or di-substituted by alkyl group having 1 to 4 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 8 carbon atoms, hydroxy group, alkoxy group having 1 to 6 carbon atoms, alkenyloxy group having 2 to 5 carbon atoms, cycloalkyloxy group having 3 to 7 carbon atoms, aralkyloxy group having 7 to 9 carbon atoms, aryloxy group having 6 to 14 carbon atoms (e.g., phenyloxy, naphthyloxy and the like), thiol group, alkylthio group having 1 to 6 carbon atoms, aralkylthio group having 7 to 9 carbon atoms, arylthio group having 6 to 14 carbon atoms (e.g., phenylthio, naphthylthio and the like), sulfo group, cyano group, azido group, nitro group, nitroso group, halogen atom (e.g., fluorine, chlorine, bromine, iodine) and the like.
(1-4) Preferable Examples of R1 
In the formulas, R1 is preferably an optionally substituted heterocyclic group, more preferably an optionally substituted pyridyl, an optionally substituted oxazolyl, an optionally substituted thiazolyl or an optionally substituted triazolyl. R1 is particularly preferably pyridyl, oxazolyl, thiazolyl or triazolyl, each of which optionally having 1 or 2 substituents selected from alkyl having 1 to 3 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, furyl, thienyl, phenyl and naphthyl. As used herein, furyl, thienyl, phenyl and naphthyl may have 1 or 2 substituents selected from alkyl having 1 to 3 carbon atoms, alkoxy having 1 to 3 carbon atoms, halogen (e.g., fluorine, chlorine, bromine, iodine and the like) and haloalkyl having 1 to 3 carbon atoms.
Preferable examples of R1 include an optionally substituted heterocyclic group and an optionally substituted cyclic hydrocarbon group, which are represented by the following formulas: 
These groups may have 1 or 2 substituents selected from phenyl, furyl, thienyl and alkyl having 1 to 4 carbon atoms. The phenyl, furyl and thienyl may have 1 or 2 substituents selected from alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro, haloalkyl having 1 to 6 carbon atoms and haloalkoxy having 1 to 6 carbon atoms. The alkyl having 1 to 4 carbon atoms may have 1 or 2 substituents selected from alkoxy having 1 to 6 carbon atoms, halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro, haloalkyl having 1 to 6 carbon atoms and haloalkoxy having 1 to 6 carbon atoms.
R1 is more preferably a group represented by the following formula: 
wherein Ph is an optionally substituted phenyl group and Rxe2x80x3 is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms.
The substituent for the phenyl group represented by Ph and the alkyl group having 1 to 6 carbon atoms represented by Rxe2x80x3 is, for example, alkoxy having 1 to 6 carbon atoms, halogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitro, haloalkyl having 1 to 6 carbon atoms or haloalkoxy having 1 to 6 carbon atoms. The number of substituent is, for example, 1 to 3.
(2) Definition of X
In the formulas, X is a bond or a group represented by xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94NR6xe2x80x94(R6 is hydrogen atom or optionally substituted alkyl group), of which a bond, xe2x80x94CH(OH)xe2x80x94 and xe2x80x94NR6xe2x80x94 are preferable, and a bond and xe2x80x94NR6xe2x80x94 are more preferable.
As used herein, as the alkyl group of the xe2x80x9coptionally substituted alkyl groupxe2x80x9d represented by R6, an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl and the like, is mentioned. The alkyl group may have 1 to 3 substituents at substitutable positions and examples of such substituent include halogen (e.g., fluorine, chlorine, bromine, iodine), alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t.-butoxy and the like), hydroxy group, nitro group and acyl group having 1 to 4 carbon atoms (e.g., alkanoyl group having 1 to 4 carbon atoms such as formyl, acetyl, propionyl and the like).
(3) Definition of n and Y
In the formulas, n is an integer of 1 to 3, preferably 1 or 2.
In the formulas, Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or xe2x80x94NR7xe2x80x94(R7 is hydrogen atom or optionally substituted alkyl group), of which xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR7xe2x80x94 are preferable. As used herein, the xe2x80x9coptionally substituted alkyl groupxe2x80x9d represented by R7 is exemplified by those recited as the above-mentioned xe2x80x9coptionally substituted alkyl groupxe2x80x9d represented by R6.
(4) Definition of Ring A
In the formulas, ring A is a benzene ring, and the benzene ring optionally has 1 to 3 substituents at substitutable positions. Examples of such substituent include alkyl group, optionally substituted hydroxy group, halogen atom, optionally substituted acyl group, nitro group and optionally substituted amino group, all of which are exemplified by those recited as the substituent for hydrocarbon group and heterocyclic group represented by R1.
Said substituent is preferably an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom.
In the formulas, the partial structural formula 
is preferably or 
(5) Definition of p
In the formulas, p is an integer of 1 to 8, preferably an integer of 1 to 3.
(6) Definition of R2 
In the formulas, the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R2 is exemplified by those recited as the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
The xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R2 is exemplified by those recited as the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1.
In the formulas, R2 is preferably an optionally substituted hydrocarbon group. R2 is more preferably an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic aliphatic hydrocarbon group or an optionally substituted aromatic hydrocarbon group, particularly preferably an optionally substituted alkyl having 1 to 4 carbon atoms, an optionally substituted phenylalkenyl group having 8 to 10 carbon atoms or an optionally substituted aryl group having 6 to 14 carbon atoms.
The substituent that these hydrocarbon groups may have is preferably halogen atom, alkoxy group having 1 to 4 carbon atoms, aryloxy group having 6 to 14 carbon atoms and aromatic heterocyclic group (e.g., furyl, thienyl). The number of substituent is, for example, 1 to 3.
(7) Definition of q and m
In the formulas, q is an integer of 0 to 6, preferably 0 to 4. m is 0 or 1.
(8) Definition of R8 and R9 
In the formulas, R8 and R9 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted acyl group, or R8 and R9 may be bonded to form a ring.
The xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R8 and R9 are each exemplified by those recited as the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1.
The xe2x80x9coptionally substituted acyl groupxe2x80x9d represented by R8 and R9 are exemplified by those similar to the xe2x80x9coptionally substituted acyl groupxe2x80x9d recited as the substituent that the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 may have.
R8 and R9 may be bonded to form a 5 to 7-membered cyclic amino group. Concrete examples of cyclic amino group include 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 4-morpholino, 4-thiomorpholino and the like.
(9) Definition of R4 and R5 
In the formulas, R4 and R5 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, or R4 may be bonded to R2 to form a ring.
The xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R4 and R5 is exemplified by those similar to the aforementioned xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d of R1, with preference given to those similar to the aforementioned xe2x80x9coptionally substituted alkyl groupxe2x80x9d represented by R6 and the like.
R4 may be bonded to R2 to form a ring. The ring formed by R4 and R2 in combination is, for example, cycloalkane having 5 to 11 carbon atoms, cycloalkene having 5 to 11 carbon atoms and the like, which are specifically cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, cyclononane, cyclononene, cyclodecane, cyclodecene, cycloundecane and cycloundecene and the like.
(10) Definition of Z
In the formulas, Z is a halogen atom or OSO2R10 (R10 is alkyl group having 1 to 4 carbon atoms, aryl group having 6 to 10 carbon atoms that is optionally substituted by alkyl group having 1 to 4 carbon atoms).
As the halogen atom, fluorine, chlorine, bromine and the like are mentioned, with preference given to chlorine.
With regard to the xe2x80x9calkyl having 1 to 4 carbon atomsxe2x80x9d and xe2x80x9can aryl group having 6 to 10 carbon atoms that is optionally substituted by alkyl group having 1 to 4 carbon atomsxe2x80x9d represented by R10, the xe2x80x9calkyl having 1 to 4 carbon atomsxe2x80x9d is exemplified by those mentioned above which are recited as R6. The aryl group having 6 to 10 carbon atoms of the xe2x80x9caryl group having 6 to 10 carbon atoms that is optionally substituted by alkyl group having 1 to 4 carbon atomsxe2x80x9d is exemplified by phenyl, naphthyl and the like, with preference given to phenyl.
Preferable examples of Z include chlorine, methanesulfonyl, toluenesulfonyl and the like, with preference given to chlorine.
(11) (E) Form and/or (Z) Form Compound
The compounds represented by the formulas (II) and (III) have an (E) form and a (Z) form at imino bond. The compound includes such (E) form and (Z) form as single compounds, and a mixture thereof.
(12) Preferable Examples
Preferable compounds represented by the formulas (III) and (V), which are produced according to the production method of the present invention, include the following compounds:
(1) (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-benzyloxyimino]-4-phenylbutanoic acid or a salt thereof,
(2) (E)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-benzyloxyimino]-8-phenyloctanoic acid or a salt thereof,
(3) (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-benzyloxyimino]-4-phenylbutylamide or a salt thereof.
The salt of the compound represented by the formula (I), (II), (III), (IV) or (V) (hereinafter sometimes to be briefly referred to as compound (I), (II), (III), (IV) or (V)) is preferably a pharmacologically acceptable salt. Examples of the salt include, salts formed with inorganic base, salts formed with organic base, salts formed with inorganic acid, salts formed with organic acid, salts formed with basic or acidic amino acid and the like.
Preferable examples of the salt formed with inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; and aluminum salt, ammonium salt and the like.
Preferable examples of the salt formed with organic base include salts formed with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.
Preferable examples of the salt formed with inorganic acid include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of the salt formed with organic acid include salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
Preferable examples of the salt formed with basic amino acid include salts formed with arginine, lysin, ornithine and the like, preferable examples of the salt formed with acidic amino acid include salts formed with aspartic acid, glutamic acid and the like.
Of the above-mentioned salts, sodium salt, potassium salt, hydrochloride and the like are preferable.
The reaction between compound (I) and compound (II) (hereinafter sometimes to be briefly referred to as reaction A) is carried out in an amide in the presence of a metal alkoxide.
As used herein, the metal alkoxide is, for example, alkali metal C1-6 alkoxide. Examples thereof include tert-butoxide, methoxide, ethoxide and the like of sodium, potassium and lithium. The metal alkoxide is preferably alkali metal C1-6 alkoxide, more preferably sodium tert-butoxide.
While the amount of a metal alkoxide to be used varies depending on the amide to be used and reaction temperature, it is generally 0.5-20 equivalents, preferably 2-20 equivalents, more preferably 2-5 equivalents, relative to compound (II). That is, the metal alkoxide is used in an amount of 50-2000 mol %, preferably 200-2000 mol %, more preferably 200-500 mol %, relative to compound (II).
As the amides, for example, N,N-dimethylformamide, acetamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like are used. The amides preferably include N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone, particularly preferably N,N-dimethylacetamide. Only one kind of these amides or two or more kinds thereof may be used at a suitable mixing ratio.
In the reaction of compound (I) with compound (II), the equivalent ratio of compound (I):compound (II) is about 5:1-about 1:5, preferably about 1:1-2. That is, compound (II) is used in an amount of about 20-about 500 mol %, preferably about 100-about 200 mol %, relative to compound (I).
The reaction of compound (I) with compound (IV) (hereinafter sometimes to be briefly referred to as reaction B) is carried out in an amide in the presence of a metal carbonate.
As used herein, the metal carbonate is exemplified by sodium, potassium, lithium, calcium, cecium, rubidium and the like. The metal carbonate is preferably alkali metal carbonate, more preferably potassium carbonate.
The metal carbonate is used in an amount of generally 20-500 mol %, preferably 50-200 mol %, relative to compound (IV).
The amides are exemplified by those recited as the amides for the aforementioned reaction A. Of those, N,N-dimethylformamide and the like are preferable.
In the reaction of compound (I) with compound (IV), the equivalent ratio of compound (I):compound (IV) is about 5:1-about 1:5, preferably about 1:1-2. That is, compound (IV) is used in an amount of about 20-about 500 mol %, preferably about 100-about 200 mol %, relative to compound (I).
The order of charging reaction A and reaction B is not particularly limited as long as it does not influence the reaction.
For example, (a) a metal alkoxide or metal carbonate may be added to a mixture of compound (I) with compound (II) or a mixture of compound (I) with compound (IV), respectively or (b) a mixture of compound (I) with compound (II) or a mixture of compound (I) with compound (IV), or each one of them may be added successively to metal alkoxide or metal carbonate, respectively, which is dissolved or suspended in advance in amides, or (c) compound (II) or compound (IV) is added to metal alkoxide or metal carbonate, respectively, which is dissolved or suspended in advance in amides to prepare a solution or suspension, and compound (I) dissolved or suspended in amides may be added thereto.
The reaction temperature of reaction A and reaction B varies depending on the kind of metal alkoxide, metal carbonate and the amides to be used. The temperature may be in the range of from xe2x88x9278xc2x0 C. to the boiling point of amides, preferably from xe2x88x925xc2x0 C. to the boiling point of amides (e.g., 200xc2x0 C.). The reaction temperature is more preferably xe2x88x925xc2x0 C. to 80xc2x0 C.
The reaction time of reaction A and reaction B is, for example, 0.5-20 hours.
In the reaction A and reaction B, the reaction may be carried out in the presence of a quaternary ammonium salt, such as tetrabutylammonium bromide and the like; an alkali or alkali metal salt, such as potassium iodide, sodium iodide, potassium bromide, sodium bromide and the like; crown ether and the like, to promote the reaction.
The compound (III) obtained in reaction A may be amidated as noted below to produce compound (V). 
The amidation reaction is carried out according to a method known per se. That is, a method wherein compound (III) and a compound represented by the formula
HNR8R9xe2x80x83xe2x80x83(VI)
wherein the symbols in the formula are as defined above, or a salt thereof (the salt is exemplified by those recited as the salt of compound (I) and the like) are directly condensed using a condensing agent (e.g., dicyclohexylcarbodiimide and the like), a method wherein a reactive derivative of compound (III) and compound (VI) are reacted appropriately, a method described in Organic Functional Group Preparations, Second Edition, pp. 316-355, ACADEMIC PRESS INC., or other method is used.
As used herein, the reactive derivative of compound (III) is exemplified by acid anhydride, acid halide (acid chloride, acid bromide), imidazolide, a mixed acid anhydride (e.g., anhydride with methyl carbonate, ethyl carbonate or isobutyl carbonate and the like) and the like. For example, when an acid halide is used, the reaction is carried out in the presence of a base in a solvent that does not influence the reaction. As the base, for example, triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, potassium carbonate and the like are mentioned. As the solvent that does not influence the reaction, for example, halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane and the like, ethyl acetate, water and the like are mentioned. These solvents may be mixed for use at a suitable mixing ratio. The amount of compound (VI) to be used is 1-10 molar equivalents, preferably 1-3 molar equivalents, relative to compound (III). The reaction temperature is generally from xe2x88x9230xc2x0 C. to 100xc2x0 C., and the reaction time is 0.5-20 hours. When a mixed acid anhydride is used, compound (III) and chlorocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate and the like) are reacted in the presence of a base (e.g., triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, potassium carbonate and the like), and then the reaction mixture is reacted with compound (VI). The amount of compound (VI) to be used is 1-10 molar equivalents, preferably 1-3 molar equivalents, relative to compound (III). The reaction temperature is generally from xe2x88x9230xc2x0 C. to 100xc2x0 C., and the reaction time is 0.5-20 hours.
The compound (III) and compound (V) thus obtained can be separated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, treatment with activated carbon and the like. That is, the treatment after reaction may be extraction by a method known per se, such as extraction with a mixed solvent of an organic solvent insoluble or sparingly soluble in water and water. The organic solvent insoluble or sparingly soluble in water may be any as long as the objective compound can be dissolved, and is preferably aromatic hydrocarbons such as toluene; esters such as ethyl acetate and the like; ethers such as diisopropyl ether, t.-butyl methyl ether, tetrahydrofuran and the like.
Where necessary, employed is a washing process comprising maintaining the reaction mixture after completion of the reaction basic for dissolution of the objective compound in a salt form in water, washing the obtained solution with an organic solvent insoluble or sparingly soluble in water, and making the solution acidic to return the salt to the objective compound in a free form. Further employed is a washing process comprising washing an organic solvent insoluble or sparingly soluble in water, which contains the objective compound in a free form, with brine having an optional concentration or water.
In addition, the objective compound may be purified by a method known per se, such as recrystallization and the like. The recrystallization may be conducted utilizing the difference in solubility under heating conditions and in a solvent (e.g., diisopropyl ether, t.-butyl methyl ether, n-hexane and the like) in which the objective compound is insoluble or sparingly soluble at a particular temperature, or utilizing the difference in solubility of a mixed solvent, by dissolving the objective compound in a solvent (e.g., tetrahydrofuran, acetone and the like) in which the compound is soluble or easily soluble, and adding a solvent (e.g., diisopropyl ether, t.-butyl methyl ether, n-hexane, water and the like) in which the objective compound is insoluble or sparingly soluble, and the like.
The starting material compound used for each of the aforementioned reactions can be synthesized by, for example, the following method.
The compound (I) can be synthesized by, (1) reacting butanedione oxime with benzaldehyde in the presence of an acid to convert the compound to N-oxide, reacting this compound with xalyl chloride, phosphorus oxychloride and the like to give a chloromethyl compound, according to the method described in Chemical and Pharmaceutical Bulletin, vol. 19, p. 2050 (1970), (2) converting the chloromethyl compound to a benzaldehyde compound by reacting the chloromethyl compound with p-hydroxybenzyl alcohol in the presence of a base according to the method described in Journal of Chemical Society, Chemical Communications, vol. 9, p. 582 (1988), or reacting the chloromethyl compound with p-hydroxybenzaldehyde in the presence of a base according to the method described in Journal of Organic Chemistry, vol. 57, p. 589 (1992), reducing this compound with a reducing agent, such as sodium borohydride and the like, according to the method described in Tetrahedron Letters, vol. 28, p. 2473 (1987), to synthesize a hydroxymethyl compound, and (3) reacting this compound with thionyl chloride and the like, according to the method described in Journal of Medicinal Chemistry, vol. 29, p. 1589 (1986). The compound (I) can be also synthesized according to a method similar to these methods.
The compound (II) and compound (IV) can be synthesized according to the method described in Pharmazie, vol. 38, p. 313 (1983) or Acta Crystallographica, vol. C50, p. 78 (1994), namely, according to a method comprising reacting ketone and hydroxyamine in the presence of a base, or a method similar to these methods.
The compound (I), compound (II) and compound (IV) thus obtained may be respectively used for the production method of the present invention after separation and purification by a known means, or used as a reaction mixture for the production method of the present invention.